WO2011073172A1 - Ethynyl derivatives - Google Patents
Ethynyl derivatives Download PDFInfo
- Publication number
- WO2011073172A1 WO2011073172A1 PCT/EP2010/069593 EP2010069593W WO2011073172A1 WO 2011073172 A1 WO2011073172 A1 WO 2011073172A1 EP 2010069593 W EP2010069593 W EP 2010069593W WO 2011073172 A1 WO2011073172 A1 WO 2011073172A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrimidine
- phenylethynyl
- tert
- butyl
- pyrazolo
- Prior art date
Links
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 50
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 21
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 230000003281 allosteric effect Effects 0.000 claims abstract description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims abstract description 13
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims abstract description 13
- 230000003287 optical effect Effects 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 138
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 9
- 201000000980 schizophrenia Diseases 0.000 claims description 9
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 208000010877 cognitive disease Diseases 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- STWIZYIJRYCGDE-UHFFFAOYSA-N 2-methyl-2-[6-(2-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]propan-1-ol Chemical compound C=1N2N=C(C(C)(CO)C)N=C2C=CC=1C#CC1=CC=CC=C1 STWIZYIJRYCGDE-UHFFFAOYSA-N 0.000 claims description 3
- SBUGGCACDAQHDM-UHFFFAOYSA-N 2-tert-butyl-6-[2-(3-fluorophenyl)ethynyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1N2N=C(C(C)(C)C)N=C2N=CC=1C#CC1=CC=CC(F)=C1 SBUGGCACDAQHDM-UHFFFAOYSA-N 0.000 claims description 3
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- AZMOMUKMXTWBLN-UHFFFAOYSA-N 4-[6-[2-(3-methylphenyl)ethynyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]morpholine Chemical compound CC1=CC=CC(C#CC2=CN3N=C(N=C3N=C2)N2CCOCC2)=C1 AZMOMUKMXTWBLN-UHFFFAOYSA-N 0.000 claims description 3
- XNJIKZWLSIRDKA-UHFFFAOYSA-N 6-(2-phenylethynyl)-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C1CCCN1C1=NN2C=C(C#CC=3C=CC=CC=3)C=NC2=N1 XNJIKZWLSIRDKA-UHFFFAOYSA-N 0.000 claims description 3
- AFEVBVRCZOWJJF-UHFFFAOYSA-N 6-(2-phenylethynyl)triazolo[1,5-a]pyridine Chemical compound C1=CC2=CN=NN2C=C1C#CC1=CC=CC=C1 AFEVBVRCZOWJJF-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
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- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- FULXPKRQIAMYGK-UHFFFAOYSA-N 2-tert-butyl-6-(2-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine 6-(2-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine Chemical compound C(C)(C)(C)C1=NN2C(C=CC(=C2)C#CC2=CC=CC=C2)=N1.C1(=CC=CC=C1)C#CC=1C=CC=2N(C1)N=CN2 FULXPKRQIAMYGK-UHFFFAOYSA-N 0.000 claims 1
- IMMIPOOXSOXTFB-UHFFFAOYSA-N 2-tert-butyl-6-(2-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine 6-(2-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C(C)(C)(C)C1=NN2C(N=CC(=C2)C#CC2=CC=CC=C2)=N1.C1(=CC=CC=C1)C#CC=1C=NC=2N(C1)N=CN2 IMMIPOOXSOXTFB-UHFFFAOYSA-N 0.000 claims 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XEHVFKKSDRMODV-UHFFFAOYSA-N ethynyl Chemical class C#[C] XEHVFKKSDRMODV-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 1
- 108010038445 metabotropic glutamate receptor 3 Proteins 0.000 description 1
- 108010038422 metabotropic glutamate receptor 4 Proteins 0.000 description 1
- 108010038450 metabotropic glutamate receptor 6 Proteins 0.000 description 1
- 108010038449 metabotropic glutamate receptor 7 Proteins 0.000 description 1
- 108010038448 metabotropic glutamate receptor 8 Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- WUKSVVOCYHTIMV-UHFFFAOYSA-N methyl 3-amino-1h-pyrazole-5-carboxylate Chemical compound COC(=O)C=1C=C(N)NN=1 WUKSVVOCYHTIMV-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical class COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 210000002265 sensory receptor cell Anatomy 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- POFDSYGXHVPQNX-UHFFFAOYSA-N triazolo[1,5-a]pyrimidine Chemical compound C1=CC=NC2=CN=NN21 POFDSYGXHVPQNX-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to et
- Y is N or C-R 2 ;
- R 4 is a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atoms, optionally substituted by 1 to 3 groups, selected from halogen, lower alkyl, lower alkoxy or NRR';
- R 1 is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, lower cycloalkyl or is heterocycloalkyl optionally substituted with hydroxy or alkoxy;
- Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12(12), 1845-1852 doi: 10.1517/13543776.12.12.1845 .
- alkoxy denotes a group -O-R' wherein R' is lower alkyl as defined above.
- R 4 is a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atoms, optionally substituted by 1 to 3 groups, selected from halogen, lower alkyl, lower alkoxy or NRR';
- R 4 is a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atoms, optionally substituted by 1 to 3 groups, selected from halogen, lower alkyl, lower alkoxy or NRR';
- R 1 is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, lower cycloalkyl or is heterocycloalkyl optionally substituted with hydroxy or alkoxy;
- a 6-ethynyl-[l,2,4]triazolo[l,5-a]pyrimidine of formula IC can also be obtained by condensation of an appropriately substituted lH-l,2,4-triazol-5-amine 39 with 2-bromomalonaldehyde 40 in AcOH to give the corresponding 6-bromo-[l,2,4]triazolo[l,5-a]pyrimidine 21. Sonogashira coupling of 21 with trimethylsilyl acetylene 10 yields the corresponding 6- trimethylsilanylethynyl-[l,2,4]triazolo[l,5-a]pyrimidine 41.
- Graphs were plotted with the % maximal stimulatory using XLfit, a curve fitting program that iteratively plots the data using Levenburg Marquardt algorithm.
- Step 3 2-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[l,5-a]pyrimidine
- N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (example 39, step 1) (5.8 g, 19.1 mmol) was dissolved in 30 ml of toluene and Lawesson's reagent (7.7 g, 19.1 mmol, 1 equiv.) was added at room temperature. The reaction mixture was stirred for 48 hours at 110°C. The crude product was purified by flash chromatography by directly loading the cooled toluene reaction mixture onto a 300 g silica gel column and eluting with heptane:ethyl acetate 100:0 -> 80:20.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (17)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ599553A NZ599553A (en) | 2009-12-17 | 2010-12-14 | Ethynyl derivatives |
| JP2012543676A JP5763094B2 (ja) | 2009-12-17 | 2010-12-14 | エチニル誘導体 |
| AU2010332987A AU2010332987B2 (en) | 2009-12-17 | 2010-12-14 | Ethynyl derivatives |
| EP10790960.8A EP2513102B1 (en) | 2009-12-17 | 2010-12-14 | Ethynyl derivatives |
| UAA201207427A UA107002C2 (ru) | 2009-12-17 | 2010-12-14 | Этинильные производные |
| RU2012128551/04A RU2553461C2 (ru) | 2009-12-17 | 2010-12-14 | Производные этинила |
| ES10790960.8T ES2551582T3 (es) | 2009-12-17 | 2010-12-14 | Derivados de etinilo |
| CN201080057081.9A CN102686589B (zh) | 2009-12-17 | 2010-12-14 | 乙炔基衍生物 |
| MX2012006789A MX2012006789A (es) | 2009-12-17 | 2010-12-14 | Derivados de etinilo. |
| SG2012044814A SG181779A1 (en) | 2009-12-17 | 2010-12-14 | Ethynyl derivatives |
| KR1020127018589A KR101407856B1 (ko) | 2009-12-17 | 2010-12-14 | 에티닐 유도체 |
| CA2780155A CA2780155A1 (en) | 2009-12-17 | 2010-12-14 | Ethynyl derivatives |
| BR112012014770A BR112012014770A2 (pt) | 2009-12-17 | 2010-12-14 | derivados de etinila |
| IL219371A IL219371A (en) | 2009-12-17 | 2012-04-23 | Ethylene History - (s-Triazolo / Pyrzolo) [a – 5,1] (Pyridine / Pyrimidine) and Pharmaceuticals Containing Them |
| MA34890A MA33802B1 (fr) | 2009-12-17 | 2012-05-24 | Dérivés d'éthynyle |
| ZA2012/04429A ZA201204429B (en) | 2009-12-17 | 2012-06-15 | Ethynyl derivatives |
| HK12112004.5A HK1171225A1 (en) | 2009-12-17 | 2012-11-23 | Ethynyl derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09179719 | 2009-12-17 | ||
| EP09179719.1 | 2009-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011073172A1 true WO2011073172A1 (en) | 2011-06-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2010/069593 WO2011073172A1 (en) | 2009-12-17 | 2010-12-14 | Ethynyl derivatives |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US8586581B2 (ru) |
| EP (1) | EP2513102B1 (ru) |
| JP (1) | JP5763094B2 (ru) |
| KR (1) | KR101407856B1 (ru) |
| CN (1) | CN102686589B (ru) |
| AR (1) | AR079467A1 (ru) |
| AU (1) | AU2010332987B2 (ru) |
| BR (1) | BR112012014770A2 (ru) |
| CA (1) | CA2780155A1 (ru) |
| CL (1) | CL2012001596A1 (ru) |
| CO (1) | CO6531478A2 (ru) |
| CR (1) | CR20120269A (ru) |
| EC (1) | ECSP12011977A (ru) |
| ES (1) | ES2551582T3 (ru) |
| HK (1) | HK1171225A1 (ru) |
| IL (1) | IL219371A (ru) |
| MA (1) | MA33802B1 (ru) |
| MX (1) | MX2012006789A (ru) |
| MY (1) | MY162998A (ru) |
| NZ (1) | NZ599553A (ru) |
| PE (1) | PE20121443A1 (ru) |
| RU (1) | RU2553461C2 (ru) |
| SG (1) | SG181779A1 (ru) |
| TW (1) | TWI448465B (ru) |
| UA (1) | UA107002C2 (ru) |
| WO (1) | WO2011073172A1 (ru) |
| ZA (1) | ZA201204429B (ru) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013045380A2 (en) | 2011-09-30 | 2013-04-04 | F. Hoffmann-La Roche Ag | Pharmaceutically acceptable mglur5 positive allosteric modulators and their methods of identification |
| EP2636668A1 (en) * | 2010-11-05 | 2013-09-11 | Otsuka AgriTechno Co., Ltd | Ethynylphenylamidine compound or salt thereof, method for producing same, and fungicide for agricultural and horticultural use |
| US8957213B2 (en) | 2011-04-26 | 2015-02-17 | Hoffman-La Roche Inc. | Ethynyl compounds |
| CN104684911A (zh) * | 2012-09-27 | 2015-06-03 | 霍夫曼-拉罗奇有限公司 | 芳基乙炔基衍生物 |
| JP2015536959A (ja) * | 2012-11-07 | 2015-12-24 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | トリアゾロ化合物 |
| US11034699B2 (en) | 2015-07-15 | 2021-06-15 | Hoffmann-La Roche Inc. | Ethynyl derivatives |
| US11059766B2 (en) | 2015-06-03 | 2021-07-13 | Hoffmann-La Roche Inc. | Ethynyl derivatives |
| US11242349B2 (en) | 2016-07-18 | 2022-02-08 | Hoffmann-La Roche Inc. | Ethynyl derivatives |
| US12006323B2 (en) | 2015-07-15 | 2024-06-11 | Hoffmann-La Roche Inc. | Ethynyl derivatives |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA110862C2 (uk) * | 2011-10-07 | 2016-02-25 | Ф. Хоффманн-Ля Рош Аг | Похідні етинілу як алостеричні модулятори метаботропного рецептора глутамату mglur 5 |
| CA2879489A1 (en) * | 2012-10-18 | 2014-04-24 | F.Hoffmann-La Roche Ag | Ethynyl derivatives as modulators of mglur5 receptor activity |
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| WO2003042211A1 (en) * | 2001-11-15 | 2003-05-22 | Smithkline Beecham Corporation | Phenyl substituted triazoles and their use as selective inhibors of akl5 kinase |
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